The present invention relates to polycarbonates bearing pendant primary amines for medical applications, and more specifically to polycarbonates having a repeat unit derived from serinol, threoninol and like compounds.
A desirable feature of an antimicrobial material for biomedical applications is biodegradability and/or biocompatibility. Peptide based antimicrobials are easily degraded in vivo, and have short blood circulation times, which in part can be attributed to the presence of primary amine groups in their structures. Antimicrobial peptides, however, are disadvantaged by high production costs. Less expensive alternatives are needed.
Polycarbonates bearing protonated amine groups are attractive as biodegradable and/or biocompatible substitutes for peptide-based antibiotics. As one example, cyclic carbonate monomers derived from L-threoninol, in which the primary amine group was protected with a t-butoxy carbonyl (tBoc) group or with a benzyloxy carbonyl (Z) group, were prepared and polymerized by metal catalyzed ring opening polymerization to form homopolymers comprising pendant primary amines (F. Sanda, et al., Macromolecules 2001, 34, pages 1564-1569). However, homopolymers are typically weak antimicrobial agents because of the high charge density.
Other polymers bearing primary amine groups, such as those derived from meth(acrylate) monomers, are limited in their use because of non-biodegradability and/or high cytotoxicity. Many of the existing materials are non-selective biocides (i.e., destructive to microbial and mammalian cells).
Due to the astronomical increase in the development cost of new drug candidates, exploration of innovative tactics for the encapsulation and release of existing drugs has emerged as one of the key approaches to improve the efficacy of treatment. Strategies focusing on the development of novel nano-sized drug delivery platforms have been shown to have tremendous impact in improving the bioavailability of the drugs. Such improvements over the bioavailability of therapeutics will enable effective administration of existing pool of approved drugs.
Comprehensive strategies to manage the drug administration are important, particularly in the following aspects. With respect to antibiotics, the emergence of bacterial resistance and the low rate of regulatory clearance of new antibiotics has created a need to deliver existing antibiotics so as to maximize their efficacy. With respect to non-steroidal anti-inflammatory drugs (NSAID) the increase in the global ageing population has generated a need for optimal use of NSAIDs to alleviate pain. In both of the above-mentioned situations, improper use could lead to long-term detrimental effects. Improper infectious disease management exponentially increases the chances of development of microbial resistance. In the case of NSAIDs, potential development of other side-effects such as gastrointestinal complications may surface.
Thus, biodegradable, biocompatible polymers bearing pendant primary amines were sought as alternatives to peptide based materials for antimicrobial applications and/or the delivery of biologically active substances, such as anionic drugs. Other desirable properties of the polymers include the capability of forming injectable solutions and/or crosslinked hydrogel layers, and high activity against Gram negative microbes in addition to Gram positive microbes.